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REVIEW ARTICLE
Year : 2012  |  Volume : 8  |  Issue : 6  |  Page : 67-71

The role of intensity modulated radiotherapy in advanced oral cavity carcinoma


1 Head and Neck Unit, Royal Marsden Hospital, SW3 6JJ; The Institute of Cancer Research, 237 Fulham Road, SW3 6JB, London, United Kingdom
2 Head and Neck Unit, Royal Marsden Hospital, SW3 6JJ, London, United Kingdom

Date of Web Publication24-Jan-2012

Correspondence Address:
S A Bhide
Head and Neck Unit, Royal Marsden Hospital, Downs Road, Sutton, SM2 5PT
United Kingdom
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.92218

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 > Abstract 

It is increasingly being recognized that oral cavity cancer incidences are rising globally. Furthermore, these tumors represent a high risk group of tumors comparative to other head and neck tumor sub-sites and have a high preponderance of occult nodal metastases. Surgery alone leads to excellent outcomes in early stage disease. Advanced tumors require adjuvant radiotherapy with or without concomitant chemotherapy. Irradiation using 3D conformal radiotherapy results in high incidence of late radiation side-effects. Xersostomia and mandibular osteoradionecrosis result in most significant effects on patients' quality of life. Intensity modulated radiotherapy (IMRT) is an advanced approach to 3-D treatment planning and conformal therapy (3D-CRT). It optimizes the delivery of irradiation to irregularly-shaped volumes and has the ability to produce concavities in radiation treatment volumes and hence enables sparing of normal tissue while delivering adequate doses to the tumor volumes. In this manuscript, we discuss the advantages of IMRT based on review of published peer reviewed literature.

Keywords: Intensity modulated radiotherapy, oral cavity cancer, carcinoma


How to cite this article:
Bhide S A, Ahmed M, Newbold K, Harrington K J, Nutting C M. The role of intensity modulated radiotherapy in advanced oral cavity carcinoma. J Can Res Ther 2012;8, Suppl S2:67-71

How to cite this URL:
Bhide S A, Ahmed M, Newbold K, Harrington K J, Nutting C M. The role of intensity modulated radiotherapy in advanced oral cavity carcinoma. J Can Res Ther [serial online] 2012 [cited 2019 May 25];8:67-71. Available from: http://www.cancerjournal.net/text.asp?2012/8/6/67/92218


 > Introduction Top


Oral cavity cancer is the sixth most common cancer worldwide. [1] Incidences vary widely across geographical areas with the UK demonstrating a relatively low incidence of 3500 cases per year, [2] compared to parts of South East Asia where a third of all male cancers in India originate in the oral cavity. [3] Etiological factors for squamous cell oral cavity cancer (OCC) such as high tobacco and alcohol consumption, and betel quid chewing, may account for some of these geographical variations. [4] Recently infection with human papilloma virus has been identified as a causal factor for the rising incidence of oropharyngeal cancers in non-smokers. However, the relationship with oral cavity cancer is not yet established. [5]

It is increasingly being recognized that oral cavity cancer incidences are rising globally. Furthermor, these tumors represent a high risk group of tumors comparative to other head and neck tumor sub-sites and have a high preponderance of occult nodal metastases with an incidence of 20-40% on pathological examination of the clinically node-negative neck. [6],[7]


 > Treatment of Oral Cavity Cancers Top


External beam radiotherapy is used in the treatment of OCC, primarily in the post-operative setting but also as first definitive treatment when surgery is felt to be inappropriate. [8] In these early stage patients, risk stratification is based on thickness and grade of tumor. [9] Patients with oral tongue tumors or floor of mouth tumors with a clinically node-negative neck require surgical resection of the primary lesion and elective neck dissection at the very least. In 1972, a study by Lindberg demonstrated that the lymph node groups most frequently involved in patients with carcinoma of the oral cavity are the jugulodigastric and midjugular nodes (levels II and III). In patients with carcinoma of the floor of the mouth, anterior oral tongue, and buccal mucosa, the nodes most frequently involved are in the submandibular triangle (level I). Lindberg also noted that cancers frequently metastasize to both sides of the neck and can skip the submandibular and jugulodigastric nodes, metastasizing first to the midjugular region.

Supra-omohyoid neck dissection (dissection of nodal compartments level I to III) offers similar rates of locoregional control and survival as a modified radical neck dissection. [10] Most surgical groups advocate the use of an extended supra-omohyoid dissection in oral tongue tumors and deem it compulsory for the node positive patient due to the risk of skip metastasis to nodal compartment level IV while some groups will recommend the extended supra-omohyoid dissection for floor of mouth tumors in addition to tongue tumors. [11] Tumors approaching the midline require dissection of the contralateral neck. Post-operative radiotherapy is administered in selected high risk groups. [12]


 > Radiotherapy for Oral Cavity Cancers Top


Stage III and IV tumors of the oral cavity generally require bilateral oral cavity and neck irradiation following surgery. The acute toxicity from bilateral oral cavity irradiation is severe, and the majority of patients develop grade 2/3 oral mucositis and dysphagia. However, these acute effects are self-limiting and it is the permanent nature of the late effects which become more problematic. Sixty-six percent of patients with stage III disease and 58% patients with stage IV undergoing appropriate surgical management and post-operative radiotherapy will survive five years or longer and are deemed cured beyond this point. They are therefore susceptible to lifelong consequences of irradiation.


 > Intensity Modulated Radiotherapy Top


Intensity modulated radiotherapy (IMRT) is an advanced approach to 3-D treatment planning and conformal therapy (3D-CRT). It optimizes the delivery of irradiation to irregularly-shaped volumes and has the ability to produce concavities in radiation treatment volumes. Typically for head and neck cancer the clinical target volume 1 (CTV1), which includes the primary tumor and the involved nodes receives a higher radiation dose as compared to the clinical target volume 2 (CTV2). The different doses to CTV1 and 2 can be delivered simultaneously, while sparing the parotid salivary glands and the spinal cord. In the head and neck region, IMRT has a number of potential advantages: (i) it allows for greater sparing of normal structures such as salivary glands, esophagus, optic nerves, brain stem, and spinal cord; [13],[14] (ii) it allows treatment to be delivered in a single treatment phase without the requirement for matching additional fields to provide tumor boosts and eliminates the need for electron fields to the posterior (level II, V) neck nodes; (iii) it offers the possibility of simultaneously delivering higher radiation doses to regions of gross disease and lower doses to areas of microscopic disease, the so-called simultaneous integrated boost (SIB-IMRT). [15]

Salivary sparing

The most common late effect of bilateral oral cavity irradiation is xerostomia which can affect dentition, speech, swallowing and mastication. Radiation for squamous cell OCC requires high doses in the region of 66-70 Gy for radical treatment and 60Gy in the post-operative setting. These dose levels far exceed the tolerance doses of salivary tissue, resulting in a high incidence of xerostomia for this group of patients. Eisbruch et al. (1999) were able to demonstrate substantial preservation of flow rates for unstimulated saliva with a mean threshold dose to the parotid at <24Gy, and <26Gy for stimulated saliva. [16] Stimulated salivary flow recovered over a period of approximately 12 months. Unilateral parotid dose levels above these values saw virtually no recovery of salivary flow, confirming that the parotid gland behaves as a parallel organ exhibiting a threshold effect. Partial volume thresholds also displayed a threshold effect and the volume of parotid tissue able to receive 30Gy (V 30 ) was 45%. Nutting et al were able to demonstrate a 50% reduction in subjective xerostomia rates with IMRT compared to the conventionally treated patients by maintaining a mean dose to the contralateral parotid gland of 26Gy. [17] Parotid-sparing IMRT for oropharyngeal tumors was achieved in most cases by sparing the contralateral parotid gland where the contra-lateral parapharyngeal space (upper part of level II) and parotid gland were judged to be at very low risk of harboring occult metastases. Further sparing of salivary gland tissue was achieved by applying a dose constraint to the anterior oral cavity and sparing this structure in the optimization process. Contra lateral parotid, sub-mandibular glands and oral cavity can be spared when treating well lateralized tumors (buccal mucosa, retro-molar trigone, lateral alveolar ridge) of the oral cavity. Sparing the contra lateral organs at risk is difficult when treating mid-line tumors of the oral cavity in order to deliver adequate doses to the bilateral parapharyngeal spaces and lymph node levels Ib and II. Ahmed et al in a planning study demonstrated that parotid sparing is achievable in the treatment of advanced squamous cell OCC, particularly in patients who have not undergone surgery, but also in post-operative patients where the superior border of delineation can be lowered to below the hard palate with the use of a bite block and providing the neck is maintained in a neutral position, [Figure 1]. [18] In addition, Miah et al have demonstrated that the incidence of late grade II xerostomia can be reduced by sparing bi-lateral superficial parotid glands, while delivering adequate doses to the parapharyngeal spaces and level II lymph nodes in tumors of the oropharynx. [19]
Figure 1: Parotid sparing (glands outlined in purple) that can be achieved using IMRT (B) compared to 3D-CRT (A)

Click here to view


Six studies investigating the use of IMRT in OCC have been published to date. Chen et al performed a non-randomized retrospective comparison of patients treated with IMRT vs. 3D-CRT. [20] The rates of grade 2 xerostomia at two years were 36% vs. 82% respectively. The grade 2 xersotomia was 29% as reported by Gomez et al. [21] The other studies failed to report the rates of xerostomia. Parotid dose levels are not the only factor to influence xerostomia rates, particularly subjective xerostomia scores. The parotid glands along with the sub-mandibular gland represent the major salivary glands and produce the bulk of saliva. The minor salivary glands which are scattered throughout the oral cavity produce less than 10% of the total saliva volume but crucially contribute more than 70% of total mucins. [22] Mucins serve as mucosal lubricants. Their molecular structure binds water effectively thus maintaining the mucosal membranes in a state of hydration. [23] The need to spare the mucin-producing minor and submandibular salivary glands became apparent after the realization that parotid-sparing alone achieves modest patient-reported gains in xerostomia. [24],[25] Hence, most IMRT OP studies have since defined a cost function for oral-cavity sparing in their optimization process. As an at risk structure a dose constraint of 30Gy or less is applied. As this structure is part of the target volume for OCC, this dose constraint cannot be applied in IMRT planning of these patients. This may have significant implications on subjective xerostomia scores and highlights the need to assess not only salivary flow rates but also QOL measurements or subjective xerostomia scores.


 > Osteoradionecrosis of Mandible Top


A more problematic late effect of radiation is osteoradionecrosis (ORN). Osteoradionecrosis, a process of bone and soft tissue necrosis, arising as a result of radiation-induced hypocellularity, hypoxia and hypovascularity, results in an area of non-healing bone. ORN can lead to pain, infection and sequestration of bone and, in extreme cases, the development of fistulae. [26] ORN is the most severe complication of bone irradiation, most commonly affecting the body of the mandible which may be a result of the relatively poor vascularity of this region. [27] Spontaneous ORN is dose dependent (> 60 Gy) and relates to the volume of mandible within the treatment field. [28],[29] Trauma-related ORN can occur at lower doses. Reuther et al were able to demonstrate a significant correlation between radiation dose and extent of ORN. Most ORN lesions measuring 2 cm or more occurred at doses of 60 Gy or higher. At this dose level, there was also a preponderance of smaller ORN lesions. Below 60 Gy most lesions were < 2 cm in size. [30] A similar study demonstrated increasing incidences of ORN with increased doses of radiotherapy. Few cases of ORN were observed below 50Gy. [31] A more recent study by Lee et al found that the risk of ORN either traumatic or spontaneous correlated to the mandible receiving a radiation dose of BED equivalent 102.6 Gy (2) or higher. In their series of 198 patients, 45% of which were OCC cases and the remainder OP cases, the overall ORN rates were 6.6%. They observed no cases of ORN in patients receiving doses below this threshold. Hence, they concluded that radiation to the mandible at doses of 54Gy or higher (at conventional fractionation) was a risk factor for the development of ORN. [32] Conventional planning frequently causes hot-spots within parts of the mandible outside the target volume (mandible PRV), and the greater the size of the areas of high dose, the greater the subsequent risk of ORN.Other studies have defined 'the delivery of >95% of the total radiation dose to the whole bone diameter' as a risk factor and also the presence of teeth in the high dose area. [33] The incidence of severe osteoradionecrosis after treatment for head and neck cancer is 5-15% depending on the dose to the mandible and factors such dental hygiene. [33],[34] Studies have demonstrated that the dose to the mandible can be minimized without affecting the dose to the target volumes. [33],[35]

The study by Ahmed et al assessed the volumes of mandible exposed to high doses represented by the V50, 55, 60. IMRT was able to reduce, not only the dose maxima to the mandible PRV, to significantly lower values than those seen in conventional planning but also the volumes of mandible receiving 50, 55 and 60 Gy. Furthermore, in the IMRT plans a rim of mandible along the buccal cortex was spared from the high isodose curves of 95% to 100, [Figure 2]. [18] Based on the data from the above studies, one would anticipate this dosimetric advantage seen with IMRT to translate into a clinical advantage, with a potential to reduce the risk of ORN. This clinical benefit was not conclusively demonstrated in the RTOG-022 IMRT study which demonstrated ORN rates of 6%. [36] Similarly studies of IMRT for OCC have demonstrated the risk of late ORN of around 5%. [21],[37] Two studies in OP cancer have demonstrated substantial benefit with IMRT for the prevention of ORN. The first of these studies reviewed all patients treated with parotid sparing IMRT in prospective studies at a single institution. The patients adhered to a strict dental policy of dental evaluation, patient education and radiation guards for dental metal work. So far not a single case of ORN has been identified. [35] Similarly Studer et al demonstrated a low ORN incidence of 1.3% with parotid sparing IMRT. [33] Both studies used an oral cavity dose constraint as the majority of tumors were oropharyngeal in origin. However, the latter study group also included 18 OCC patients. A subsequent study by this group compared 58 IMRT treated OCC patients with 33 historical controls (treated with 3DCRT). Patients treated with definitive RT alone demonstrated higher locoregional recurrence rates with IMRT, than those treated with 3DCRT while patients receiving combined modality treatment with surgery and IMRT demonstrated the best local control rates. Once more an oral cavity dose constraint was used and no cases of ORN after 22 months have been described. This is not strictly possible in the treatment of OCC where the oral cavity is the principal target volume and more compromise local control. Other risk factors for ORN aside from the volume of irradiated mandible, and dose maxima to the mandible, need to be considered. The importance of dental care is undoubtedly a contributory factor. This will impact on the risk of dental caries and minimize the requirement for dental extractions. IMRT may also diminish this risk due to improved saliva flow. In the planning study described above, the parotid sparing potential of IMRT for OCC has been demonstrated. The sparing of minor salivary tissue was not attempted due to the 'at risk' tumor volume. The extent to which these varying factors bear an impact on ORN is difficult to define but it is likely that a combination of mandible sparing, salivary tissue sparing and exemplary dental care all contribute to the lowered ORN rates seen in these clinical studies.
Figure 2: Relative mandibular sparing (outer rim) that can be achieved with IMRT compared to 3D-CRT

Click here to view


Predictably, the mandibular-sparing potential of IMRT diminishes in patients who require a rim resection or segmental mandiblectomy. One would expect to see even less of a benefit in patients with alveolar tumors where the bulk of the mandible (most of which will be reconstructed) is encompassed within PTV1. There is evidence of higher rates of ORN in T4 tumors. [30],[31] This is felt to be due to a combination of factors including the type of surgery, the high radiation dose in adjacent mandible and hypoxia in the surgical bed. Lee's study which demonstrated radiation BED to be a risk factor for ORN showed that the most significant risk factor for ORN was in fact previous mandibular surgery. [32] Hence although it is technically more difficult to spare the mandible in these patients, mandible sparing is more likely to be necessary. The other key risk factor for ORN in these patients is the addition of chemotherapy to their radiation treatment. Increasingly chemoradiation is being used in patients with positive margins or with evidence of extracapsular spread. [38] Patients not suitable for surgery receive chemoradiation as definitive treatment unless contra-indicated. Studies have demonstrated higher ORN incidences in this group of patients with one study from the University of Chicago demonstrating an ORN incidence of 18.4% in patients with advanced OCC receiving chemoradiation. Some patients in this study had received IMRT but the majority had been treated with older radiation techniques. [39]


 > Treatment Outcomes Top


IMRT plans have steep dose gradients on account of the attempt to spare the organs at risk. The sharp dose gradients increase the likelihood of a geographical miss and the possibility of reduced loco-regional controls. Chen et al, in a non-randomized retrospective comparison of patients treated with IMRT vs. 3D-CRT showed equivalent outcomes. [20] The five other studies that used IMRT for OCC demonstrated equivalent if not superior outcomes for IMRT when compared to historical controls. [21],[37],[40],[41],[42]


 > Conclusion Top


IMRT of advanced oral cavity tumors offers the potential to reduce the risks of xerostomia and ORN through parotid and mandibular sparing. This can be performed without compromising on target volume coverage and hence treatment outcomes.

 
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